Happy 60th Birthday: The science that makes transplantation work

By Daniel M. Davis

Sixty years ago today, the world’s top science journal Nature published an article just 3½ pages long, which won a Nobel Prize for its lead author Peter Medawar and more importantly put doctors on the right path for making transplantation surgery the life-saver that it is today. Up until that point, the idea of using one person’s body parts to save the life of another was little more than a fanciful idea in science fiction. Some mavericks had claimed success in transplantation; they were perhaps lucky once but more likely, they were lying. The thinking at the time was that doctors just needed to work out the right surgical procedure to get transplantation to work. But they were wrong; Medawar’s landmark 3½ pages in Nature showed that whatever the actual procedure — even if the cutting and sewing was perfect — the transplantation would usually still fail. There’s a fundamental aspect of human biology that causes human tissue to be rejected when moved from one person to another. Medawar’s 3½ pages in Nature showed a way in which the problem could be solved.

Seeing the agony of airmen suffering from drastic skin burns at a War Wounds Hospital in Oxford in 1940 focused Medawar’s mind on solving the transplantation problem. “A scientist who wants to do something original and important must experience, as I did, some kind of shock that forces upon his intention the kind of problem that it should be his duty and will become his pleasure to investigate,” he said later.

From the moment he witnessed the hospital scene, Medawar ‘worked like a demon’, according to his wife Jean. Through careful observations of patients (and experiments on animals) he set out to examine — more carefully than anyone previously — what happened when skin was grafted from one person to another (or between animals). One breakthrough observation he made was when the same patient needed a second skin graft. He noted that if the second transplant used skin from the same (unrelated) donor as the first transplant, then this second graft was rejected very quickly. This kind of rejection is the hallmark of an immune system reaction; the recipient’s immune cells could recognise the graft as being like the one before and attacked it rapidly. It’s the same with say, the flu virus; when you recover from flu, you’ll be strong at fighting the same flu virus again, but not a different version of flu or some other virus. This with other observations he made amounted to unequivocal evidence that a reaction from the recipient’s immune cells caused graft rejection. He showed that transplantation wasn’t just about getting the surgery right; fundamentally it was a problem caused by an immune reaction. This shifted everyone’s thinking onto the right path.

Even so, this was still merely a prelude to his seminal experiment reported in those 3½ pages in Nature — published just a few months after Watson and Crick famously presented the iconic double helix structure of DNA in the same journal. In these few pages Medawar gave us a way to solve the problem of transplantation. That is, he found a way to transplant skin from one animal to another so that it would not be rejected — there would be no immune reaction at all — even if the animals were unrelated.

Medawar — with his research team of two others, Rupert Billingham and Leslie Brent — injected cells from one type of mouse into unborn foetal mice. They discovered that after birth, when tested as adults, the injected mice were able to accept skin from the unrelated mouse strain whose cells had been injected. Medawar’s wife, Jean, dubbed the treated mice ‘Super-mice’. These were startling results; the problem of transplantation had a solution. The Super-mice had become tolerant to skin grafts from unrelated mice whose cells they had been exposed to when foetuses. The implication was that, early in life, the immune system learns to not attack our own cells and tissues.

At first, Medawar would often deny that his research had any direct medical implications because his research didn’t reveal a method for human transplantation. His way of circumventing the natural barrier to transplantation had only been shown to work with young animals and he was cautious about claiming too much medical significance for his basic research. But in time, it became clear that transplantation would become a life-saving surgical procedure. Although his way of solving the difficulties in transplantation could not be a routine procedure for humans, the research began a sixty year-long adventure, involving thousands of scientists, in understanding our immune system. The details cannot be paraphrased with suitable brevity here, but genetic matching between people and the use of immune suppressive drugs make clinical transplantation a life-saving reality, and both directly build upon Medawar’s insights.

Happy 60th Birthday to these ground-breaking experiments that proved to be of exceptional medical importance — and changed the way we understand the human body.